Focus on Filgotinib in Rheumatoid Arthritis: A Trial-Based Review

Janus kinases (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway is involved in pathophysiologic cascade of a notable number of rheumatic diseases. The development of JAK inhibitors has expanded treatment choices in rheumatoid arthritis (RA) with a sustained class-effect efficacy. Filgotinib is a novel selective inhibitor of JAK1 isoform licensed for use in RA and ulcerative colitis. In this review we aim to present an analysis of filgotinib’s efficacy and drug-specific safety warnings. Patients with RA with or without concomitant conventional synthetic Disease-Modifying Antirheumatic Drugs (csDMARDs) (naïve or experienced) and those who have failed biologic Disease-Modifying Antirheumatic Drugs (bDMARDs) were examined in randomised clinical trials. Filgotinib was also tested against placebo, methotrexate, or adalimumab. Long-term extension trials provide insights for up to four years of continuous filgotinib administration. Beneficial effects are depicted in both disease activity parameters and quality of life indexes in moderate or severe RA with a longitudinal efficacy. In head-to-head comparison with adalimumab, filgotinib 200 mg was non-inferior. Adverse effects alerts are marked by the elevated risk of infectious adverse effects with the exception of herpes zoster infection, which has a low incidence.


INTRODUCTION
Janus kinases (JAKs) are immunomodulatory mediators involved in the JAK/signal transducer and activator of transcription (STAT) pathway and participate in autoimmune and inflammatory cytosolic and nucleic signals in close synergy with cytokines and cytokines receptors. 1emantically, their name derives from the roman god Janus identified as the god of beginnings or doorways implying their key role in autoimmune rheumatic diseases.The JAK/STAT pathway is activated by extracellular signalling molecules (cytokines) which bind to the outer domain of a membrane receptor.These receptors also possess an intracellular domain who acts as an anchor for JAKs docking.Once cytokines link to the receptors the associated JAKs are activated and phosphorylate tyrosine residues on the receptor which then recruits STAT proteins.When employed, the STAT proteins act as transcription factors, migrate to the nucleus and modulate specific genes.Cytokines binds to their respective receptors with great selectivity which are also uniquely associated with a pair of JAKs.These pairs are formed through combinations of the four members of JAK family, namely JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). 2 Several known disease-specific cytokines exert their pathophysiological actions through JAK/STAT mechanisms; interleukin (IL)-6, involved in the development of rheumatoid arthritis (RA), is associated with JAK1, JAK2 and TYK2 3 while IL-12/IL-23, implicated in the pathogenesis of spondylarthritis (SpA) spectrum, binds to JAK2 and TYK2. 2,4he discovery of the pathogenetic role of JAK/STAT pathway led to the development of JAK inhibitors (JAKi) with the intention to block the pathophysiologic cascade and effectively treat patients with inflammatory diseases.6][7][8] Tofacitinib was the first JAK1, JAK2, and JAK3 inhibitor discovered, and is currently approved for treatment of inflammatory arthritides [RA, ankylosing spondylitis (AS), psoriatic arthritis (PsA), juvenile idiopathic arthritis] and ulcerative colitis (UC). 7,9Baricitinib mitigates arthritic symptomatology for patients with rheumatoid arthritis by inhibiting JAK1 and JAK2, 10 and is also licensed for atopic dermatitis and alopecia areata. 6The third JAK inhibitor developed was upadacitinib, which selectively inhibits JAK1 isoform contrary to tofacitinib and baricitinib. 11Upadacitinib is an authorised therapeutic option for patients with RA, PsA, axial SpA, UC, and atopic dermatitis. 8he newest tsDMARD with eclectic JAK1 inhibitory mode of action is filgotinib (FIL).This molecule proved efficacious in patients with RA and UC which enabled its EMA approval in 2020. 5In this article we comprehensively review current clinical trial data and evaluate the use of FIL for its presently authorized indications with particular emphasis in rheumatoid arthritis.

FILGOTINIB IN RHEUMATOID ARTHRITIS Effectiveness in phase II/III trials
Filgotinib in methotrexate-resistant RA Primary studies to investigate FIL's effectiveness in RA were conducted in patients who could not achieve low disease activity or disease remission with methotrexate (MTX).DARWIN 1, a phase IIb, 24-week, randomized clinical trial (RCT) divided 594 patients into six FIL treated groups (50/100/200 mg daily or 25/50/100 mg twice daily) and one placebo group to establish efficacious dosage (Table 1). 12A significant difference was observed in the American College of Rheumatology (ACR)20 response (12 weeks) in FIL 200 mg daily, 100 mg daily and 100 mg twice daily treated arms versus placebo.For ACR 20/50/70 responses, the higher the FIL dose, the highest the number of patients achieving these responses was.All FIL-treated arms at 24 weeks mastered a greater ACR50, ACR70 and Health Assessment Questionnaire-Disability Index (HAQ-DI) in comparison to placebo arm.(all p<0.05).At week 12, 66 patients either on placebo or on FIL <100 mg total daily dose who did not achieve an ACR20 response, were reassigned TITLE to receive 100 mg total daily dose, and achieved better ACR20/50/70 responses.Both clinical assessment scores, Disease Activity Score (DAS) 28 [C-reactive protein (CRP)] and Clinical Disease Activity Index (CDAI) showed a significant dose-response decrease in all FIL treated patients (except 50 mg FIL in CDAI) at week 24.This dose-response relationship depicted in DARWIN 1 established the efficacy of 100 mg and 200 mg FIL doses over lower ones.Another RCT explored the impact of FIL in disease activity parameters in patients with moderately or severely active RA already under treatment with MTX.Combe et al. in their phase III trial randomised patients into four treatment groups, FIL 100 mg daily, FIL 200 mg daily, Adalimumab (ADA) 40 mg biweekly or placebo for 52 weeks (Table 1). 13FINCH 1 trial (phase III RCT) assessed the Japanese sub-population from the original pool of 1755 patients of Combe et al up to 24 weeks (Table 1). 14or the original population, primary endpoint, ACR20 response, was met for significantly more patients in the FIL plus MTX groups versus the placebo plus MTX group [76.6% for FIL 200 mg and 69.8% for FIL 100 mg versus 49.9% for placebo (all p<0.001)].Key secondary points, HAQ-DI and DAS28(CRP) <2.6, also performed significantly better for FIL compared to placebo at 12 weeks.At 24 weeks radiographic measurements were favourable for the FIL groups (p<0.05).Concerning head-to-head comparison with ADA, only FIL 200 mg was non-inferior for DAS28(CRP) ≤3.2 at 12 weeks. 13he Japanese sub-population had consistent results with the original study population for the primary and key secondary outcomes. 14lgotinib in unresponsive/intolerant to bDMARDs RA FINCH 2 study uniquely explored the effects of FIL in patients with moderate to severe RA who were refractory to one or more biologic disease-modifying antirheumatic drugs (bDMARDs), receiving concomitant stable treatment with csDMARDs (Table 1). 15This phase III RCT included 449 patients, randomised to receive FIL 200 mg, FIL 100 mg or placebo for 24 weeks.Primary endpoint, ACR20, was met for 66.0% and 57.5% of FIL, 200 mg and 100 mg, respectively, and 31.1% of placebo treated patients, proving a significant difference.Furthermore, key secondary outcomes, namely DAS28(CRP) (<2.6 and <3.2) and HAQ-DI presented significant superiority for FIL group as compared to placebo at 12 and 24 weeks.
Filgotinib in MTX-naïve RA In FINCH 3 study, a phase III RCT, FIL (100 mg or 200 mg) plus MTX outweighed MTX monotherapy in MTX naïve patients when ACR20/50/70, DAS28(CRP)<2.6 and HAQ-DI responses were considered (all p<0.05) at 24 weeks (Table 1). 16Furthermore, patients on any FIL dose plus MTX performed better on Short Form 36-Physical Component Score (SF-36 PCS) and had less radiographic progression versus patients on MTX alone, while Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT-F) scores were interchangeable.
Filgotinib monotherapy in RA FIL as stand-alone, once daily, 24-weeks therapy was firstly explored in a phase II RCT with three actively treated and a placebo arm, the DARWIN 2 study (Table 1). 17DARWIN 2 recruited 283 patients with moderate to severe active RA who had failed MTX treatment and underwent a minimum of four weeks wash out period prior to study initiation.Primary outcome was ACR20 response to treatment at week 12, which was achieved in all FIL arms (50 mg, 67%; 100 mg, 66%; 200 mg, 73%) in comparison to placebo (29% all p<0.0001).A similar pattern was followed by ACR50 responses at 12 weeks for FIL-treated patients, while patients receiving the highest FIL doses were more likely to reach an ACR70 response.Placebo and FIL 50 mg treated patients who failed to reach the ACR20 goal were re-randomised to FIL 100 mg at week 12 and exhibited a similar ACR20/50/70 response to the original 100 mg arm at week 24.The proportion of patients with ACR20/50 responses was sustained throughout the study, and even increased in the case of ACR70.DAS28(CRP), CDAI, Simplified disease activity index (SDAI), EULAR "good" responses and Health-Related Quality of Life (HRQoL) significantly improved in all FIL arms at week 12 compared to placebo.DARWIN 2 displayed that FIL dose and disease activity were generally inversely related.Westhovens et al. in their phase III RCT randomised 1252 RA patients with limited or no MTX exposure to receive either FIL (in two distinct doses) in combination with MTX or monotherapy with FIL/methotrexate (FINCH 3 study, Table 1). 16For the ACR20 response, FIL 200 mg monotherapy when compared to methotrexate alone showed no superiority at week 24, contrary to week 52 when FIL significantly prevailed.Furthermore, comparison in both arms for SF-36 and FACIT-F proved neutral, however they differed significantly in modified Total Sharp Score (mTSS), HAQ-DI in favor of FIL and a higher number of patients receiving FIL achieved a DAS28(CRP)<2.6 and ACR50/70 responses at weeks 24 and 52. 16ng-term extension studies Useful insights into FIL's effectiveness and safety in the long run, are provided by long term extension studies (LTE).DARWIN 3 (Table 1) study recruited eligible patients from DARWIN 1 and 2 for an additional period of four years, while they received treatment with FIL 200 mg total daily dose with or without MTX.This trial conferred results emphasising FIL's longitudinal benefit in RA activity scores with an ACR20/50/70 response of By the study end, approximately half of the patients on any group achieved a DAS28(CRP)<2.6. 18However, DARWIN 3 study results were hindered by the high discontinuation rate (46.7% in FIL plus MTX group and 43.8% in FIL monotherapy group) mainly attributed to adverse effects and should be viewed with caution.FINCH 4 is the extension study of FINCH 1 with a currently ongoing horizon of 6 years follow-up (Table 1).Preliminary data up to 48 weeks are provided for the two group of patients studied (FIL 100 mg plus MTX, FIL 200 mg plus MTX) after rerandomising the ADA group from the parent study.At 48 weeks, 94% of patients in the FIL 200 mg plus MTX arm and 92% of FIL 100 mg plus MTX arm managed an ACR20 response.ACR 50/70 were 75%/57% and 83%/58% for FIL 200 mg plus MTX and FIL 100 mg plus MTX respectively.Disease activity measured as DAS28(CRP)<2.6 was reported for 81% of patients treated with FIL 200 mg and 74% of patients in the FIL 100 mg arm. 19fety FIL proved to be well tolerated during DARWIN 1 and DARWIN 2 phase IIb trials with similar rate of adverse events reported across all study groups for each study. 12,17erious infections occurred in 6 (one received placebo) and 4 (one received placebo) patients in DARWIN 1 and 2 respectively, while herpes zoster infection occurred in collectively 6 patients (one received placebo).DARWIN 1 reports two cardiovascular events namely a stroke and a myocardial infraction during study duration. 12ata from DARWIN 3 trial, which investigated adverse events for up to 4 years of FIL's continued use, revealed a low exposure-adjusted incidence rates (EAIRs) per 100 patient-years of exposure (PYE) for any serious infection (0.6 in FIL plus MTX group and 1.7 in FIL monotherapy group).Similar low EAIRs are for herpes zoster infection (1.3 and 1.5 per 100 PYE in the FIL plus MTX and monotherapy groups, respectively) and major cardiovascular events (MACE) (0.2 per 100 PYE for both arms).For all infectious adverse effects combined in DARWIN 3, calculated EAIRs were 16.3 in the FIL plus MTX arm and 15.9 in FIL monotherapy arm. 18On the contrary, in the phase III trial performed by Combe et al., patients with RA treated with FIL or ADA experienced more infections and serious infections versus patients receiving placebo.Herpes zoster infection was reported in 0.4% of FIL or placebo treated patients and 0.6% of ADA treated.Furthermore, venous thromboembolism occurred in one patient from FIL group and two patients from placebo group and MACE occurred in four patients (one in FIL, two in ADA and one in placebo arm).All in all, integrated results from DARWIN 1-3 and FINCH 1-4 studies outline a higher rate of infectious adverse effects (apart from her-pes zoster infection) among FIL treated patients versus placebo for the placebo-controlled time. 20Calculated EAIRs for deaths were similar for FIL and placebo (0.6/100PYE) while herpes zoster infections, MACE, and venous thromboembolism were infrequently reported. 20

FILGOTINIB IN OTHER INFLAMMATORY DISEASES
A limited number of studies examined FIL's efficacy in mitigating arthritic symptomatology in patients with SpA.These studies were phase II RCTs and provided beneficial evidence.For AS in TORTUGA trial (Table 2), FIL provided a clear benefit, as patients on FIL achieved a significant reduction in Ankylosing Spondylitis Disease Activity Score (ASDAS) compared to placebo treated patients.Furthermore, a higher proportion of patients reached an Assessment of SpondyloArthritis international Society (ASAS) 20 and ASAS40 response in the FIL arm versus the placebo arm. 21On the other hand, EQUATOR trial was designed to test FIL's potential as a therapeutic agent in patients with PsA (Table 2).Results show that more patients in the FIL arm achieved an ACR20/50/70 response compared with placebo and these were all significant differences.FIL also managed greater improvements in Disease Activity Index for Psoriatic Arthritis (DAPSA) scores and psoriasis [measured with Psoriasis Area and Severity Index 75(PASI75)] versus placebo. 22owever, both TORTUGA trial and EQUATOR trial had a small number of participants, and more studies are needed to confirm these results. 21,22nflammatory bowel diseases are another therapeutic target for JAKi with tofacitinib and upadacitinib already being used successfully in UC. 7,8 Gastroenterologists include FIL in their official armamentarium for the treatment of UC based on positive results from SELECTION and SELECTIONLTE trials. 23,24For Crohn's disease, results were ambiguous; in DIVERGENCE trial FIL performed poorly and did not meet trial's endpoints, 25 while in FIRZROY trial more patients receiving FIL achieved disease remission compared to placebo. 26CONCLUSION Filgotinib is a selective inhibitor of JAK1 isoform and the latest of this class to receive official approval for use in rheumatoid arthritis.Beneficial effects are depicted in both disease activity parameters and quality of life indexes in moderate or severe RA with or without background csDMARDs and in patients who have failed bDMARDs.In head-to-head comparison with ADA, FIL 200 mg was non-inferior.LTE studies illustrate a longitudinal efficacy profile of filgotinib while safety profile is marked by the elevated risk of infectious adverse effects, with the exception of herpes zoster infection which has a low incidence.